US20220332726A1 - Nitroxide derivative of rock kinase inhibitor - Google Patents

Nitroxide derivative of rock kinase inhibitor Download PDF

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US20220332726A1
US20220332726A1 US17/298,676 US202017298676A US2022332726A1 US 20220332726 A1 US20220332726 A1 US 20220332726A1 US 202017298676 A US202017298676 A US 202017298676A US 2022332726 A1 US2022332726 A1 US 2022332726A1
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Wang Shen
Kui Feng DANG
Chao Zhang
Chunming Chen
Li Hong SHAN
Wen Ding
Xin Wang
Jia Chen MI
Ya Bo SUN
Xia Xin SHENG
Jia Lei SHEN
Yong Li
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Vivavision Shanghai Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a new heterocyclic ROCK kinase inhibitor, and more specifically, the invention relates to a nitroxide derivative of a ROCK kinase inhibitor. These compounds can be used to treat glaucoma and retinal diseases.
  • Rho-associated coiled-coil protein kinase belongs to the AGC (PKA/PKG/PKC) family of serine-threonine kinases.
  • ROCK-I also known as p160ROCK or ROK ⁇
  • ROCK-II ROK ⁇
  • Rho belongs to the GTPase superfamily of small molecule monomers and is a mammalian gene homolog of the Ras superfamily. The reorganization of the cellular actin skeleton is adjusted by the most important effector molecule Rho-kinase in the downstream of Rho (Rho-associated coiled-coil containing protein kinase, ROCK).
  • Rho is widely involved in a series of biological processes such as cell mitosis, cytoskeleton adjustment, smooth muscle cell contraction, nerve regeneration, tumor cell infiltration, and regulation of apoptosis. After activation, Rho/ROCK can act on a variety of substrates, resulting in biological processes.
  • MLC myosin light chain
  • MLCP myosin light chain phosphatase
  • the phosphorylation level of MLC is an important factor in determining the degree of smooth muscle contraction.
  • Myosin light chain kinase (MLCK) phosphorylates the Ser-19 site of MLC, leading to smooth muscle contraction; inhibition of MLCP can further enhance the phosphorylation of MLC and the contraction of smooth muscle.
  • ROCK can phosphorylate MLC itself to cause myofilament contraction; at the same time, ROCK can phosphorylate MLCP and inactivate MLCP, resulting in increased phosphorylation of MLC in the cell cytoplasm, thus indirectly promoting myofilament contraction.
  • Rho-kinase activity in animal models has shown multiple benefits in the treatment of human diseases, including cardiovascular diseases such as pulmonary hypertension, high blood pressure, atherosclerosis, cardiac hypertrophy, high intraocular pressure, cerebral ischemia, cerebral vasospasm, etc., and central nervous system disorders such as neuronal degeneration, and tumors.
  • cardiovascular diseases such as pulmonary hypertension, high blood pressure, atherosclerosis, cardiac hypertrophy, high intraocular pressure, cerebral ischemia, cerebral vasospasm, etc.
  • central nervous system disorders such as neuronal degeneration, and tumors.
  • ROCK expression and activity are elevated in spontaneously hypertensive rats, indicating that ROCK is related to the occurrence of hypertension in these animals (Involvement of Rho-kinase in hypertensive vascular disease: a novel therapeutic target in hypertension. FASEB J., 2001, 15(6):1062-4).
  • ROCK inhibitor Y-27632 can significantly reduce blood pressure in three rat hypertension models (spontaneous hypertension, renal hypertension, and deoxycorticosterone acetate salt hypertension), but has less effect on blood pressure in control rats (Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension[J]. Nature, 1997, 389(6654):990-4). Studies have also shown that ROCK inhibitors have a better effect on pulmonary hypertension (Acute vasodilator effects of a Rho-kinase inhibitor, fasudil in patients with severe pulmonary hypertension. Heart, 2005:91(3):391-2).
  • ROCK activity is an important signal transmission mechanism in leukocyte-platelet-endothelial interaction, leukocyte extravasation, and edema.
  • Excessive activation of Rho-kinase in endothelial cells can cause leakage caused by the destruction of cell-cell junctions that facilitate recruitment of inflammatory cells.
  • these evidences point to the role of ROCK in pathological conditions related to acute and chronic inflammation and autoimmune diseases (Isoform-specific targeting of ROCK proteins in immune cells. Small GTPases. 2016; 7(3):173-177).
  • the beneficial effects of ROCK inhibition in experimental models of rheumatoid arthritis and lupus are verified by animal experiments (Rho kinase inhibitors and their application to inflammatory disorders. Curr.
  • ROCK inflammatory bowel disease
  • Rhopressa netarsudil
  • Nitric oxide is an important intercellular information transmission factor. NO can be synthesized in organisms by NO synthase or released by drugs (such as nitroglycerin, Latanoprostene Bunod, nitro-containing prostaglandin drugs). NO binds to soluble guanylate cyclase (sGC) and then converts guanosine triphosphate into cyclic guanosine monophosphate (cGMP). cGMP is a second messenger regulating smooth muscle relaxation and vasodilation and many other important biological processes, such as platelet inhibition and cell growth and differentiation. NO plays an important physiological role in regulating the blood flow of the optic nerve head and IOP. In the optic nerve head, NO donors reduce vascular resistance by relaxing smooth muscles, leading to local vasodilation and increased blood flow to the optic nerve head. Conversely, damage to the NO pathway reduces blood flow to the optic nerve head, leading to ischemia.
  • drugs such as nitroglycerin, Latanoprostene Bunod,
  • NO plays an important physiological role in regulating the intraocular pressure (IOP) of the eye.
  • IOP intraocular pressure
  • eNOS endothelial nitric oxide synthase
  • TM anterior trabecular meshwork
  • mice overexpressing eNOS have lower IOP.
  • eNOS knockout mice animals with no functional eNOS gene, and therefore no endogenous eNOS
  • sGC knockout mice have increased IOP and optic nerve degeneration.
  • the mechanism by which NO reduces IOP seems to be by inhibiting actin-myosin interaction, thereby relaxing the cells in the TM and Schlemm tubes, resulting in increased water outflow and decreased IOP.
  • An object of the invention is to provide a novel small molecule drug with high activity against ROCK kinase and at the same time is a NO donor, and a preparation method and application thereof.
  • a small molecule compound of a NO donor provided by the invention is a compound shown in the following structural formula I or a stereoisomer, a geometric isomer, a tautomer, a racemate, a deuterated isotopic derivative, a hydrate, a solvate, a metabolite, or a pharmaceutically acceptable salt or prodrug thereof;
  • a ring A is a substituted or unsubstituted heteroaromatic ring
  • X is selected from (CH 2 ) n , wherein n is selected from 0, 1, 2, or 3;
  • R is a substituent of terminal —O—NO 2 ;
  • R 1 is selected from hydrogen, a hydroxyl group, a halogen, an amino group, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or a substituted or unsubstituted heteroalkyl group;
  • R 2 and R 3 are each independently selected from hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, or an amino protecting group;
  • R 2 and R 3 are connected to each other to form a substituted or unsubstituted cycloheteroalkyl group.
  • the small molecule compound of the NO donor provided by the invention is a compound shown in the following structural formula or a stereoisomer, a geometric isomer, a tautomer, a racemate, a deuterated isotopic derivative, a hydrate, a solvate, a metabolite, or a pharmaceutically acceptable salt or prodrug thereof:
  • L is a linking group selected from a substituted or unsubstituted alkylene group, a substituted or unsubstituted heteroalkylene group, a substituted or unsubstituted alkyleneoxy group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted ester group.
  • the ring A is selected from formula A or formula B;
  • R′ is one or a plurality of substituting substituent groups on the heteroaromatic ring
  • the substituent group is selected from hydrogen, a hydroxyl group, a halogen, an amino group, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted heteroalkyl group;
  • At least one of A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , and A 9 is selected from nitrogen, sulfur, or oxygen;
  • B 1 , B 2 , B 3 , B 4 , B 5 , B 6 , B 7 , B 8 , and B 9 is selected from nitrogen, sulfur, or oxygen.
  • the ring A is selected from formula Ia, formula Ib, or formula Ic;
  • R 21 is selected from hydrogen, a hydroxyl group, a halogen, an amino group, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted heteroalkyl group;
  • R 22 is selected from hydrogen, a halogen, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkoxy group.
  • the small molecule compound of the NO donor provided by the invention is a compound shown in the following structural formula or a stereoisomer, a geometric isomer, a tautomer, a racemate, a deuterated isotopic derivative, a hydrate, a solvate, a metabolite, or a pharmaceutically acceptable salt or prodrug thereof:
  • L 1 is a chemical bond or a substituted or unsubstituted alkylene group
  • L 2 is selected from a substituted or unsubstituted alkylene group, a substituted or unsubstituted alkyleneoxy group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group;
  • L 3 is a chemical bond or a substituted or unsubstituted alkyleneoxy group.
  • the small molecule compound of the NO donor provided by the invention is a compound shown in the following structural formula or a stereoisomer thereof, a geometric isomer, a tautomer, a racemate, a deuterated isotopic derivative, a hydrate, a solvate, a metabolite, or a pharmaceutically acceptable salt or prodrug:
  • n1 is 0 or a natural number
  • n2 is 0 or a natural number
  • Y is selected from a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.
  • the small molecule compound of the NO donor provided by the invention is obtained by a nitration reaction of a hydroxyl group in a compound shown in the following structure; and nitration conditions can be concentrated nitric acid, or the nitration may occur by nitric acid in acetic anhydride.
  • the small molecule compound of the NO donor provided by the invention is obtained by a nitration reaction of a halogen in a compound shown in the following structure; and nitration conditions can be a silver nitrate effect.
  • Y is a halogen
  • the small molecule compound of the NO donor provided by the invention is obtained by a coupling reaction of compounds represented by the following formula IIIa and formula IIIb;
  • Z is a halogen
  • small molecule compound of the NO donor provided by the invention is used as an inhibitor of a ROCK kinase.
  • the substituted alkyl group mentioned in the invention means that one or more of the hydrogen atoms on the carbon chain of the alkyl group are substituted by other groups.
  • the other groups referred to here can be, but are not limited to, groups such as a cycloalkyl group (substituting in a form similar to
  • any hydrogen atom on the cycloalkyl ring can also be substituted by a group such as a halogen, a cyano group, an alkyl group, a hydroxyl group, or a carboxyl group), a heterocycloalkyl group (that is, on the basis of the cycloalkyl group, at least one carbon atom on the alkyl ring is replaced by oxygen, sulfur, or nitrogen), a halogen (F, Cl, Br, or I), a carboxy group, a cyano group (—CN), a sulfonic acid group (—SO 4 ), a sulfonyl group (—SO 2 R a , R a is hydrogen, an alkyl group, an aryl group, etc.), an alkynyl group (—C ⁇ CH, —C ⁇ CR b , R b is an alkyl group, an aryl group, etc.), an amido group (—C(O)NR x R y
  • one or a plurality of carbons in the substituted alkyl group are replaced by a heteroatom such as nitrogen, oxygen, or sulfur;
  • the substituted cycloalkyl group mentioned in the invention means that one or a plurality of hydrogen atoms on the alkyl ring are replaced by other groups.
  • the other groups referred to here can be, but are not limited to, groups such as an alkyl group, a substituted alkyl group (same as above), a halogen (F, Cl, Br, or I), a carboxyl group, a cyano group (—CN), a sulfonic acid group (—SO 4 ), a sulfonyl group (—SO 2 R a , R a is hydrogen, an alkyl group, an aryl group, etc.), an alkynyl group (—C ⁇ CH, —C ⁇ CR b , R b is an alkyl group, an aryl group, etc.), an amido group (—C(O)NR x R y , R x R y is an alkyl group, an aryl group, etc.), an ester group
  • the substituted heterocycloalkyl group mentioned in the invention refers to that at least one carbon atom on the substituted cycloalkyl ring is substituted by a heteroatom such as nitrogen, oxygen, or sulfur;
  • the substituted alkenyl group mentioned in the invention means that the hydrogen atom in the structure —C ⁇ C— is replaced by other groups.
  • the other groups here can be, but are not limited to, groups such as an alkyl group, a substituted alkyl group (same as above), a halogen (F, Cl, Br, or I), a carboxyl group, a cyano group (—CN), an amido group (—C(O)NR x R y , R x R y is an alkyl group, an aryl group, etc.), an ester group (—C(O)O—R z , R z is an alkyl group, an aryl group, etc.), an aryl group, a heteroaryl group, or —O—NO 2 ;
  • the substituted alkynyl group mentioned in the invention means that the hydrogen atom in the structure —C ⁇ CH is replaced by other groups.
  • the other groups here can be, but are not limited to, groups such as an alkyl group, a substituted alkyl group (same as above), a halogen (F, Cl, Br, or I), a carboxyl group, a cyano group (—CN), an amido group (—C(O)NR x R y , R x R y is an alkyl group, an aryl group, etc.), an ester group (—C(O)O—R z , R z is an alkyl group, an aryl group, etc.), an aryl group, a heteroaryl group, or —O—NO 2 ;
  • the substituted alkylene group mentioned in the invention means that one or a plurality of the hydrogen atoms in the —(CH 2 ) n(0, natural number) — structure are substituted by other groups.
  • the other groups referred to here can be, but are not limited to, groups such as a cycloalkyl group (substituting in a form similar to
  • any hydrogen atom on the cycloalkyl ring can also be substituted by a group such as a halogen, a cyano group, an alkyl group, a hydroxyl group, or a carboxyl group), a heterocycloalkyl group (that is, on the basis of the cycloalkyl group, at least one carbon atom on the alkyl ring is replaced by oxygen, sulfur, or nitrogen), a halogen (F, Cl, Br, or I), a carboxy group, a cyano group (—CN), a sulfonic acid group (—SO 4 ), a sulfonyl group (—SO 2 R a , R a is hydrogen, an alkyl group, an aryl group, etc.), an alkynyl group (—C ⁇ CH, —C ⁇ CR b , R b is an alkyl group, an aryl group, etc.), an amido group (—C(O)NR x R y
  • the substituted alkyleneoxy group mentioned in the invention means that one or a plurality of the hydrogen atoms in the —O—(CH 2 ) n(0, natural number) — or —(CH 2 ) n(0, natural number) —O—(CH 2 ) n(0, natural number) — structure are substituted by other groups.
  • the other groups referred to here can be, but are not limited to, groups such as a cycloalkyl group (substituting in a form similar to
  • any hydrogen atom on the cycloalkyl ring can also be substituted by a group such as a halogen, a cyano group, an alkyl group, a hydroxyl group, or a carboxyl group), a heterocycloalkyl group (that is, on the basis of the cycloalkyl group, at least one carbon atom on the alkyl ring is replaced by oxygen, sulfur, or nitrogen), a halogen (F, Cl, Br, or I), a carboxy group, a cyano group (—CN), a sulfonic acid group (—SO 4 ), a sulfonyl group (—SO 2 R a , R a is hydrogen, an alkyl group, an aryl group, etc.), an alkynyl group (—C ⁇ CH, —C ⁇ CR b , R b is an alkyl group, an aryl group, etc.), an amido group (—C(O)NR x R y
  • the substituted heteroalkylene group mentioned in the present invention refers to that one or a plurality of carbon atoms in the substituted alkylene group are replaced by a heteroatom such as nitrogen, oxygen, or sulfur;
  • the substituted aryl group mentioned in the invention means that one or a plurality of hydrogen atoms on five-membered or above aromatic rings or benzo aromatic rings of, for example, benzene, naphthalene, fluorene are replaced by other groups.
  • the other groups referred to here can be groups such as an alkyl group, a substituted alkyl group (same as above), a halogen (F, Cl, Br, or I), a carboxyl group, a cyano group (—CN), a sulfonic acid group (—SO 4 ), a sulfonyl group (—SO 2 R a , R a is hydrogen, an alkyl group, an aryl group, etc.), an alkynyl group (—C ⁇ CH, —C ⁇ CR b , R b is an alkyl group, an aryl group, etc.), an amido group (—C(O)NR x R y , R x R y is an alkyl group, an aryl group, etc.), an ester group (—C(O)O—R z , R z is an alkyl group, an aryl group, etc.), an aryl group, or a heteroaryl group.
  • heteroaryl group mentioned in the invention refers to a five-membered or above aromatic heterocycle or benzo aromatic heterocycle such as thiophene, pyrrole, pyridine, furan, imidazole, benzimidazole, or quinoline.
  • the substituted heteroaryl group mentioned in the invention means that one or a plurality of hydrogen atoms on five-membered or above aromatic heterocycles or benzo aromatic heterocycles of, for example, thiophene, pyrrole, pyridine, furan, imidazole, benzimidazole, quinoline are replaced by other groups.
  • the other groups referred to here can be groups such as an alkyl group, a substituted alkyl group (same as above), a halogen (F, Cl, Br, or I), a carboxyl group, a cyano group (—CN), a sulfonic acid group (—SO 4 ), a sulfonyl group (—SO 2 R a , R a is hydrogen, an alkyl group, an aryl group, etc.), an alkynyl group (—C ⁇ CH, —C ⁇ CR b , R b is an alkyl group, an aryl group, etc.), an amido group (—C(O)NR x R y , R x R y is an alkyl group, an aryl group, etc.), an ester group (—C(O)O—R z , R z is an alkyl group, an aryl group, etc.), an aryl group, a heteroaryl group, or —O
  • the substituted ester group mentioned in the invention refers to the form of —O—C(O)—R S —, -L s -O—C(O)—R S —, —O—C(O)—O—R S —, or -L s -O—C(O)—O—R S —, wherein L s is an alkylene group (substituted alkylene group), an aryl group, or a cycloalkyl group (substituted cycloalkyl group); and R s is an alkylene group (substituted alkylene group), an aryl group, or a cycloalkyl group (substituted cycloalkyl group).
  • Step A 2-(4-(bromomethyl)phenyl)acetic acid (Compound 1.1)
  • Step B 2-(4-(hydroxymethyl)phenyl)acetic acid (Compound 1.2)
  • Step C methyl 2-(4-(hydroxymethyl)phenyl)acetate (Compound 1.3)
  • Step E 2-(4-(((triisopropylsilyl)oxy)methyl)phenyl)acetic acid (Compound 1.5)
  • Step F (R)-4-benzyl-3-(2-(4-(((triisopropylsilyl)oxy)methyl)phenyl)acetyl)oxazolidin-2-one (Compound 1.6)
  • n-butyllithium 2.5 M, 64 mL was slowly added dropwise, and the temperature was kept at ⁇ 78° C. After the dropwise addition, stirring was performed at ⁇ 78° C. for 2 hours, then the prepared anhydrous tetrahydrofuran solution of acid chloride was slowly added via a constant-pressure dropping funnel while keeping the dropwise addition temperature at ⁇ 78° C. After the dropwise addition was completed, the reaction solution was further reacted at ⁇ 78° C. for 2 hours, and then the flask was naturally warmed to room temperature.
  • Step G 2-((S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-3-oxo-2-(4-(((triisopropylsilyl)oxy)methyl)phenyl)propyl)isoindoline-1,3-dione (Compound 1.7)
  • the reaction was kept at ⁇ 78° C. and stirring was performed for 3 hours. The temperature was naturally raised to room temperature and the reaction solution was stirred overnight. After the reaction was completed, the reaction was extracted with saturated ammonium chloride aqueous solution (400 mL). The aqueous layer was extracted with ethyl acetate (300 mL ⁇ 3), and the organic layers were combined, and washed with saturated saline water (300 mL). Drying was performed with anhydrous sodium sulfate, and filtering and spin-drying were performed to obtain a yellow solid. The yellow solid was recrystallized with an ethyl acetate/petroleum ether system to precipitate a solid. The solid was filtered, and the filter cake was washed with petroleum ether (100 mL) and spin-dried to obtain compound 1.7 (32 g, yield: 55%, white solid).
  • Step H (S)-2-((2-carboxy-2-(4-(((triisopropylsilyl)oxy)methyl)phenyl)ethyl)carbamoyl)benzoic acid (Compound 1.8)
  • Step I (S)-3-(1,3-dioxoisoindolin-2-yl)-2-(4-(((triisopropylsilyl)oxy)methyl)phenyl)propionic acid (Compound 1.9)
  • reaction solution was depressurized to dryness, and saturated aqueous ammonium chloride solution (200 mL) was added.
  • the aqueous layer was extracted with ethyl acetate (200 mL ⁇ 3), and the organic layers were combined, and washed with saturated aqueous sodium bicarbonate (300 mL) and saturated saline water (300 mL) successively. Drying was performed with anhydrous sodium sulfate, then filtering and spin-drying were performed to obtain compound 1.9 (17 g, yield: 88%, yellow solid).
  • Step J (S)-3-(1,3-dioxoisoindolin-2-yl)-N-(thieno[2,3-c]pyridin-2-yl)-2-(4-(((triisopropylsilyl)oxy)methyl)phenyl)propionamide (Compound 1.10)
  • Step K (S)-3-(1,3-dioxoisoindolin-2-yl)-2-(4-(hydroxymethyl)phenyl)-N-(thieno[2,3-c]pyridin-2-yl)propionamide (Compound 1.11)
  • Step L (S)-4-(3-(1,3-dioxoisoindolin-2-yl)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl nitrate (Compound 1.12)
  • Step M (S)-4-(3-amino-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl nitrate (Compound 1)
  • Step A methyl 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)acetate (Compound 2.1)
  • Step B methyl 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-3-(1,3-dioxoisoindolin-2-yl)propionate (Compound 2.2)
  • the temperature of the dropwise addition was controlled to be lower than ⁇ 70° C. After the dropwise addition was completed, the reaction was kept at ⁇ 78° C. and stirred for 3 hours. The reaction was monitored to be complete by TLC. Saturated ammonium chloride solution was added to quench the reaction, extraction was performed with ethyl acetate (20 mL ⁇ 3), and the organic phase was washed with saturated saline water (50 mL), dried with anhydrous sodium sulfate, filtered, spin-dried, and purified by column chromatography to obtain product 2.2 (3.6 g, yield: 78%).
  • Step C 2-((2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-2-carboxyethyl)carbamoyl)benzoic acid (Compound 2.3)
  • Step D 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-3-(1,3-dioxoisoindolin-2-yl)propionic acid (Compound 2.4)
  • Step E 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-3-(1,3-dioxoisoindolin-2-yl)-N-(isoquinolin-6-yl)propionamide (Compound 2.5)
  • Step F 3-(1,3-dioxoisoindolin-2-yl)-2-(4-(hydroxymethyl)phenyl)-N-(isoquinolin-6-yl)propionamide (Compound 2.6)
  • Step G 4-(3-(1,3-dioxoisoindolin-2-yl)-1-(isoquinolin-6-ylamino)-1-oxoprop-2-yl)benzyl nitrate (Compound 2.7)
  • Step H 3-amino-2-(4-(hydrazinomethyl)phenyl)-N-(isoquinolin-6-yl)propionamide (Compound 2)
  • Step A methyl 2-(4-vinylphenyl)acetate (Compound 3.1)
  • Methyl 2-(4-bromophenyl)acetate (11.0 g, 48.0 mmol), potassium trifluoro(vinyl)borate (7.7 g, 57.6 mmol), and cesium carbonate (31.3 g, 96.0 mmol) were dissolved in 200 mL of tetrahydrofuran and 20 mL of water. Then, bis(triphenylphosphine)palladium dichloride (674 mg, 0.96 mmol) was added to react overnight at 85° C. under nitrogen protection. The reaction was monitored to be complete by LCMS.
  • Step B methyl 2-(4-(2-hydroxyethyl)phenyl)acetate (Compound 3.2)
  • Step C methyl 2-(4-(2-((triisopropylsilyl)oxy)ethyl)phenyl)acetate (Compound 3.3)
  • Step D methyl 3-(1,3-dioxoisoindolin-2-yl)-2-(4-(2-((triisopropylsilyl)oxy)ethyl)phenyl)propionate (Compound 3.4)
  • the temperature of the dropwise addition was controlled to be lower than ⁇ 70° C. After the dropwise addition was completed, the reaction was kept at ⁇ 78° C. and stirred for 3 hours. The raw material reaction was monitored to be complete by TLC. The reaction was quenched by adding saturated ammonium chloride solution (10 mL), extraction was performed with ethyl acetate (20 mL ⁇ 3), and washing was performed with saturated saline water (50 mL). Drying was performed with anhydrous sodium sulfate, then filtering, spin-drying, and purification by column chromatography were performed to obtain product 3.4 (1.0 g, yield: 33%).
  • Step E 2-((2-carboxy-2-(4-(2-((triisopropylsilyl)oxy)ethyl)phenyl)ethyl)carbamoyl)benzoic acid (Compound 3.5)
  • Step F 3-(1,3-dioxoisoindolin-2-yl)-2-(4-(2-((triisopropylsilyl)oxy)ethyl)phenyl)propionic acid (Compound 3.6)
  • Step G 3-(1,3-dioxoisoindolin-2-yl)-N-(thieno[2,3-c]pyridin-2-yl)-2-(4-(2-((triisopropylsilyl)oxy)ethyl)phenyl)propionamide (Compound 3.7)
  • Step H 3-(1,3-dioxoisoindolin-2-yl)-2-(4-(2-hydroxyethyl)phenyl)-N-(thieno[2,3-c]pyridin-2-yl)propionamide (Compound 3.8)
  • Step I 4-(3-(1,3-dioxoisoindolin-2-yl)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)phenylacetate (Compound 3.9)
  • Step J 4-(3-amino-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)phenylacetate (Compound 3)
  • Step A compound 4.1 was synthesized using benzo[d]isothiazole-6-amine instead of thieno[2,3-c]pyridine-2-amine in step J of Example 1.
  • Step B compound 4.2 was synthesized using step K in Example 1.
  • Step C (S)-4-(1-(benzo[d]isothiazol-6-ylamino)-3-(1,3-dioxoisoindolin-2-yl)-1-oxoprop-2-yl)benzyl nitrate (Compound 4.3)
  • Step D (S)-4-(3-amino-1-(benzo[d]isothiazol-6-ylamino)-1-oxoprop-2-yl)benzyl nitrate (Compound 4)
  • Step A methyl 2-(4-(oxiran-2-yl)phenyl)acetate (Compound 5.1)
  • Step B methyl 2-(4-(2,2-dimethyl-1,3-dioxolane-4-yl)phenyl)acetate (Compound 5.2)
  • Step C methyl 2-(4-(2,2-dimethyl-1,3-dioxolane-4-yl)phenyl)-3-(1,3-dioxoisoindolin-2-yl)propionate (Compound 5.3)
  • Step D 2-((2-carboxy-2-(4-(2,2-dimethyl-1,3-dioxolane-4-yl)phenyl)ethyl)carbamoyl)benzoic acid (Compound 5.4)
  • Step E 2-(4-(2,2-dimethyl-1,3-dioxolane-4-yl)phenyl)-3-(1,3-dioxoisoindolin-2-yl)propionic acid (Compound 5.5)
  • Step F 2-(4-(2,2-dimethyl-1,3-dioxolane-4-yl)phenyl)-3-(1,3-dioxoisoindolin-2-yl)-N-(thieno[2,3-c]]pyridin-2-yl)propionamide (Compound 5.6)
  • Step G 2-(4-(1,2-dihydroxyethyl)phenyl)-3-(1,3-dioxoisoindolin-2-yl)-N-(thieno[2,3-c]pyridin-2-yl)propionamide (Compound 5.7)
  • Step H 1-(4-(3-(1,3-dioxoisoindolin-2-yl)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)phenyl)ethane-1,2-dinitrodinitrate (Compound 5.8)
  • Step I 1-(4-(3-amino-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)phenyl)ethane-1,2-dinitrate (Compound 5)
  • Step A 3-(nitrooxy)cyclobutane carboxylic acid (Compound 6.1)
  • Step B (S)-4-(3-(1,3-dioxyisoindol-2-yl)-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 3-(nitrooxy)cyclobutane-1-carboxylate (Compound 6.2)
  • Step C (S)-4-(3-amino-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)propan-2-yl)benzyl 3-(nitrooxy)cyclobutene-1-carboxylate (Compound 6)
  • Step A 2-(4-((tert-butyldimethylsilyl)oxy)phenyl)acetic acid (Compound 7.1)
  • p-hydroxyphenylacetic acid (5.0 g, 32.86 mmol) was dissolved in 400 mL of tetrahydrofuran. At 0° C., imidazole (11 g, 164.3 mmol) and tert-butyldimethylchlorosilane (13.8 g, 92.00 mmol) were added, and the reaction solution was stirred at room temperature for 2 hours. 130 mL of saturated sodium carbonate solution was added to the reaction solution, and stirring was continued for 1 hour at room temperature.
  • Step B 2-(4-((tert-butyldimethylsilyl)oxy)phenyl)benzyl acetate (Compound 7.2)
  • Step C 2-(4-((tert-butyldimethylsilyl)oxy)phenyl)-3-(1,3-dioxoisoindolin-2-yl)benzyl propionate (Compound 7.3)
  • Step D 2-(4-((tert-butyldimethylsilyl)oxy)phenyl)-3-(1,3-dioxoisoindolin-2-yl)propionic acid (Compound 7.4)
  • Step E 2-(4-((tert-butyldimethylsilyl)oxy)phenyl)-3-(1,3-dioxoisoindolin-2-yl)-N-(thieno[2,3-c]pyridin-2-yl)propionamide (Compound 7.5)
  • Step F 3-amino-2-(4-((tert-butyldimethyl)oxy)phenyl)-N-(thieno[2,3-c]pyridin-2-yl)propionamide (Compound 7.6)
  • Step G allyl(2-(4-((tert-butyldimethylsilyl)oxy)phenyl)-3-oxo-3-(thieno[2,3-c]pyridin-2-ylamino)propyl)carbamate (Compound 7.7)
  • Step H allyl(2-(4-hydroxyphenyl)-3-oxo-3-(thieno[2,3-c]pyridin-2-ylamino)propyl)carbamate (Compound 7.8)
  • Step I allyl(2-(4-(2,3-dihydroxypropoxy)phenyl)-3-oxo-3-(thieno[2,3-c]pyridin-2-ylamino)propyl)carbamate (Compound 7.9)
  • Step J allyl(2-(4-(2,3-bis(nitrooxy)propoxy)phenyl)-3-oxo-3-(thieno[2,3-c]pyridin-2-ylamino)propyl)carbamate (Compound 7.10)
  • Step K 3-(4-(3-amino-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)phenoxy)propane-1,2-dinitrate (Compound 7)
  • Step A 3-amino-2-(4-((tert-butyldimethyl)oxy)phenyl)-N-(thieno[2,3-c]pyridin-2-yl)propionamide (Compound 8.1)
  • Step B (2-(4-((tert-butyldimethylsilyl)oxy)phenyl)-3-oxo-3-(thieno[2,3-c]pyridin-2-ylamino)propyl)tert-butyl carbamate (Compound 8.2)
  • Step C (2-(4-hydroxyphenyl)-3-oxo-3-(thieno[2,3-c]pyridin-2-ylamino)propyl)tert-butyl carbamate (Compound 8.3)
  • Step D 4-(3-((tert-butoxycarbonyl)amino)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)phenyl triflate (Compound 8.4)
  • Step E (2-(4-allylphenyl)-3-oxo-3-(thieno[2,3-c]pyridin-2-ylamino)propyl)tert-butyl carbamate (Compound 8.5)
  • Step F (2-(4-(3-hydroxypropyl)phenyl)-3-oxo-3-(thieno[2,3-c]pyridin-2-ylamino)propyl)tert-butyl carbamate (Compound 8.6)
  • Step G 3-(4-(3-amino-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)phenyl)propyl nitrate (Compound 8)
  • Step A (S)-4-(3-(1,3-dioxoisoindolin-2-yl)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl-5-valerate (Compound 9.1)
  • Step B (S)-4-(3-(1,3-dioxoisoindolin-2-yl)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 5-(nitrooxy)valeric acid (Compound 9.2)
  • Step C (S)-4-(3-amino-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 5-(nitrooxy)valerate (Compound 9)
  • Step A methyl 2-(4-(4-hydroxybut-1-yn-1-yl)phenyl)acetate (Compound 10.1)
  • Step B methyl 2-(4-(4-hydroxybutyl)phenyl)acetate (Compound 10.2)
  • Step C methyl 2-(4-(4-((triisopropylsilyl)oxy)butyl)phenyl)acetate (Compound 10.3)
  • Step D methyl 3-(1,3-dioxoisoindolin-2-yl)-2-(4-(4-((triisopropylsilyl)oxy)butyl)phenyl)propionate (Compound 10.4)
  • the temperature of the dropwise addition was controlled to be lower than ⁇ 70° C. After the dropwise addition was completed, the reaction was kept at ⁇ 78° C. and stirred for 3 hours. The raw material reaction was monitored to be complete by LCMS. The reaction was quenched by adding saturated ammonium chloride solution (10 mL), extraction was performed with ethyl acetate (50 mL ⁇ 3), and washing was performed with saturated saline water (100 mL). Drying was performed with anhydrous sodium sulfate, then filtering, spin-drying, and purification by column chromatography were performed to obtain product 10.4 (2.9 g, yield: 60%). LCMS ESI(+) m/z: 538.3 (M+1).
  • Step E 2-((2-carboxy-2-(4-(4-((triisopropylsilyl)oxy)butyl)phenyl)ethyl)carbamoyl)benzoic acid (Compound 10.5)
  • Step F 3-(1,3-dioxoisoindolin-2-yl)-2-(4-(4-((triisopropylsilyl)oxy)butyl)phenyl)propionic acid (Compound 10.6)
  • Step G 3-(1,3-dioxoisoindolin-2-yl)-N-(thieno[2,3-c]pyridin-2-yl)-2-(4-(4-((triisopropylsilyl)oxy)butyl)phenyl)propionamide (Compound 10.7)
  • Step H 3-(1,3-dioxoisoindolin-2-yl)-2-(4-(4-hydroxybutyl)phenyl)-N-(thieno[2,3-c]pyridin-2-yl)propionamide (Compound 10.8)
  • Step I 4-(4-(3-(1,3-dioxoisoindolin-2-yl)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)phenyl)butyl nitrate (Compound 10.9)
  • Step J 4-(4-(3-amino-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)propan-2-yl)phenyl)butyl nitrate (Compound 10)
  • Step A methyl 2-(4-vinylphenyl)acetate (Compound 11.1)
  • Methyl 2-(4-bromophenyl)acetate (10 g, 43.65 mmol) was dissolved in 200 mL of tetrahydrofuran and 20 mL of water, potassium vinyl trifluoroborate (7 g, 52.39 mmol), cesium carbonate (28.6 g, 87.31 mmol), and bis(triphenylphosphine) palladium chloride (600 mg, 0.87 mmol) were added, and the reaction solution was stirred at 78° C. under nitrogen protection for 16 hours. The reaction solution was cooled to room temperature, 100 mL of water was added to the reaction solution, and extraction was performed with ethyl acetate (400 mL) two times.
  • Step B 2-(4-(2-hydroxyethyl)phenyl)acetic acid (Compound 11.2)
  • Step C methyl 2-(4-(2-hydroxyethyl)phenyl)acetate (Compound 11.3)
  • Step D methyl 2-(4-(2-((triisopropylsilyl)oxy)ethyl)phenyl)acetate (Compound 11.4)
  • Step E 2-(4-(2-((triisopropylsilyl)oxy)ethyl)phenyl)acetic acid (Compound 11.5)
  • Step F 2-(4-(2-((triisopropylsilyl)oxy)ethyl)phenyl)acetyl chloride (Compound 11.6)
  • Step G (R)-4-benzyl-3-(2-(4-(2-((triisopropylsilyl)oxy)ethyl)phenyl)acetyl)oxazolidin-2-one (Compound 11.7)
  • Step H 2-((R)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-3-oxo-2-(4-(2-((triisopropylsilyl)oxy)ethyl)phenyl)propyl)isoindole-1,3-dione (Compound 11.8)
  • Step I (R)-2-((2-carboxy-2-(4-(2-((triisopropylsilyl)oxy)ethyl)phenyl)ethyl)carbamoyl)benzoic acid (Compound 11.9)
  • Step J (R)-3-(1,3-dioxoisoindolin-2-yl)-2-(4-(2-((triisopropylsilyl)oxy)ethyl)phenyl)propionic acid (Compound 11.10)
  • Step K (S)-3-(1,3-dioxoisoindolin-2-yl)-N-(thieno[2,3-c]pyridin-2-yl)-2-(4-(2-((triisopropylsilyl)oxy))ethyl)phenyl)propionamide (Compound 11.11)
  • Step L (S)-3-(1,3-dioxoisoindolin-2-yl)-2-(4-(2-hydroxyethyl)phenyl)-N-(thieno[2,3-c]pyridin-2-yl)propionamide (Compound 11.12)
  • Step M (S)-4-(3-(1,3-dioxoisoindolin-2-yl)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)propan-2-yl)phenethyl nitrate (Compound 11.13)
  • Step N (S)-4-(3-amino-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl) phenethyl nitrate (Compound 11)
  • Step A (S)-3-(1,3-dioxoisoindolin-2-yl)-N-(4-fluorothieno[2,3-c]pyridin-2-yl)-2-(4-(((triisopropylsilyl))oxy)methyl)phenyl)propionamide (Compound 12.1)
  • Step B (S)-3-amino-N-(4-fluorothieno[2,3-c]pyridin-2-yl)-2-(4-(((triisopropylsilyl)oxy)methyl)phenyl)propionamide (Compound 12.2)
  • Step C (S)-allyl(3-((4-fluorothieno[2,3-c]pyridin-2-yl)amino)-3-oxo-2-(4-(((triisopropylsilyl)oxy)methyl)phenyl)propyl)carbamate (Compound 12.3)
  • Step D (S)-allyl(3-((4-fluorothieno[2,3-c]pyridin-2-yl)amino)-2-(4-(hydroxymethyl)phenyl)-3-oxopropyl)carbamate (Compound 12.4)
  • Step E (S)-allyl(3-((4-fluorothieno[2,3-c]pyridin-2-yl)amino)-2-(4-((nitrooxy)methyl)phenyl)-3-oxopropyl)carbamate (Compound 12.5)
  • Step F (S)-4-(3-amino-1-((4-fluorothieno[2,3-c]pyridin-2-yl)amino)-1-oxoprop-2-yl)benzyl nitrate (Compound 12)
  • Step A (S)-4-((tert-butyldimethylsilyl)oxy)butyl 4-(3-(1,3-dioxoisoindolin-2-yl)-1-oxo-1-(thieno[2,3-c]pyridine-2)-amino)prop-2-yl)benzyl carbonate (Compound 13.1)
  • reaction solution was diluted with dichloromethane, washed successively with saturated sodium bicarbonate, 0.5 mol/L of dilute hydrochloric acid, and saturated saline water, dried with anhydrous sodium sulfate, filtered, and purified by column chromatography to obtain light yellow oily product 13.1 (25 mg, yield: 42%).
  • Step B (S)-4-(3-(1,3-dioxoisoindolin-2-yl)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl(4-hydroxybutyl)carbonate (13.2)
  • Step C S)-4-(3-(1,3-dioxoisoindolin-2-yl)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl(4-(nitrooxy)butyl)carbonate (Compound 13.3)
  • Step D (S)-4-(3-amino-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl(4-(nitrooxy)butyl)carbonate (Compound 13)
  • Step A 2-(4-(3-(((allyloxy)carbonyl)amino)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)phenoxy)dimethyl malonate (Compound 14.1)
  • Step B allyl(2-(4-((1,3-dihydroxypropan-2-yl)oxy)phenyl)-3-oxo-3-(thieno[2,3-c]pyridin-2-ylamino)propyl)carbamate (Compound 14.2)
  • Step C allyl (2-(4-((1,3-bis(nitrooxy)prop-2-yl)oxy)phenyl)-3-oxo-3-(thieno[2,3-c]pyridin-2-ylamino)propyl)carbamate (Compound 14.3)
  • Step D 2-(4-(3-amino-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)phenoxy)propane-1,3-dinitrate (Compound 14)
  • Step A (S)-3-amino-2-(4-(hydroxymethyl)phenyl)-N-(thieno[2,3-c]pyridin-2-yl)propionamide (Compound 15.1)
  • Step B (S)-tert-butyl(2-(4-(hydroxymethyl)phenyl)-3-oxo-3-(thieno[2,3-c]pyridin-2-ylamino)propyl)carbamate (Compound 15.2)
  • Step D (S)-4-(3-((tert-butoxycarbonyl)amino)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 4-(nitrooxy))-1-carboxylic acid cyclohexane (Compound 15.4)
  • Step E (S)-4-(3-amino-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 4-(nitrooxy)cyclohexane-1-carboxylic acid (Compound 15)
  • Step B methyl 4-(2-(((tert-butyldimethylsilyl)oxy)ethyl)benzoate (Compound 16.2)
  • Step C 4-(2-(((tert-butyldimethylsilyl)oxy)ethyl)benzoic acid (Compound 16.3)
  • Step D 4-(2-(nitrooxy)ethyl)benzoic acid (Compound 16.4)
  • Step E (S)-4-(3-((tert-butoxycarbonyl)amino)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)propan-2-yl)benzyl 4-(2-(nitrooxy)ethyl)benzoate (Compound 16.5)
  • Step F (S)-4-(3-amino-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 4-(2-(nitrooxy)ethyl)benzoate (Compound 16)
  • Step A methyl 2-methyl-4-vinylbenzoate (Compound 17.1)
  • Step B methyl 4-(2-hydroxyethyl)-2-methylbenzoate (Compound 17.2)
  • Step D 2-methyl-4-(2-(nitrooxy)ethyl)benzoic acid (Compound 17.4)
  • Step E (S)-4-(3-((tert-butoxycarbonyl)amino)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 2-methyl-4-(2-(nitrooxy)ethyl)benzoate (Compound 17.5)
  • Step F (S)-4-(3-amino-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 2-methyl-4-(2-(nitrooxy))ethyl)benzoate (Compound 17)
  • Step A methyl 2-methyl-5-vinylbenzoate (Compound 18.1)
  • Step B methyl 5-(2-hydroxyethyl)-2-methylbenzoate (Compound 18.2)
  • Step D 2-methyl-5-(2-(nitrooxy)ethyl)benzoic acid (Compound 18.4)
  • Step E (S)-4-(3-((tert-butoxycarbonyl)amino)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 2-methyl-5-(2-(nitrooxy)ethyl)benzoate (Compound 18.5)
  • Step F (S)-4-(3-amino-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 2-methyl-5-(2-(nitrooxy))ethyl)benzoate (Compound 18)
  • Step B 4-((S)-3-((tert-butoxycarbonyl)amino)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl(1s,4R)-4-(nitrooxy)cyclohexane-1-carboxylic acid (Compound 19.2)
  • Step C 4-((S)-3-amino-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl(1s,4R)-4-(nitrooxy)cyclohexane-1-carboxylate (Compound 19)
  • Step B 4-((S)-3-((tert-butoxycarbonyl)amino)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl(1r,4S)-4-(nitrooxy)cyclohexane-1-carboxylic acid (Compound 20.2)
  • Step C 4-((S)-3-amino-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl(1r,4S)-4-(nitrooxy)cyclohexane-1-carboxylate (Compound 20)
  • Step C (S)-4-(3-((tert-butoxycarbonyl)amino)-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 3-((nitrooxy)methyl)benzoate (Compound 21.3)
  • Step D (S)-4-(3-amino-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 3-((nitrooxy)methyl)benzoate (Compound 21)
  • Step C (S)-4-(3-((tert-butoxycarbonyl)amino)-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 4-((nitrooxy)methyl)benzoate (Compound 22.3)
  • Step D (S)-4-(3-amino-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 4-((nitrooxy)methyl)benzoate (Compound 22)
  • Step A 3-methylenecyclobutane-1-carboxylic acid (Compound 23.1)
  • 3-methylenecyclobutane-1-carbonitrile (3.1 g, 33.7 mmol) was dissolved in 20 mL of ethanol, and an aqueous solution (20 mL) of potassium hydroxide (7.6 g, 135 mmol) was added to react at 80° C. for 3 hours. After the reaction was monitored to be complete by LCMS, the organic solvent was span off, the aqueous phase was adjusted to pH ⁇ 2 with concentrated hydrochloric acid, and extraction was performed with ethyl acetate (50 mL ⁇ 2).
  • Step B benzyl 3-methylenecyclobutane-1-carboxylate (Compound 23.2)
  • Step C benzyl 3-(hydroxymethyl)cyclobutane-1-carboxylate (Compound 23.3)
  • compound 23.2 (1.41 g, 7 mmol) was dissolved in 10 mL of tetrahydrofuran, and 2.1 mL of borane dimethyl sulfide solution (10 M) was added dropwise under an ice-salt bath. After the dropwise addition was completed, the mixture was reacted at room temperature for 1 hour. After the reaction was monitored to be complete by TLC, 7 mL of sodium hydroxide aqueous solution (3 M) and 2.4 mL of hydrogen peroxide solution (30%) were successively added in the ice-salt bath, and the reaction was continued for 2 hours at room temperature.
  • Step D 3-(hydroxymethyl)cyclobutane-1-carboxylic acid (Compound 23.4)
  • Step E 3-((nitrooxy)methyl)cyclobutane-1-carboxylic acid (Compound 23.5)
  • Step F (S)-4-(3-((tert-butoxycarbonyl)amino)-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 3-((nitrooxy)methyl)cyclobutane-1-carboxylate (Compound 23.6)
  • Step G (S)-4-(3-amino-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 3-((nitrooxy)methyl)cyclobutane-1-carboxylate (Compound 23)
  • Step A 2-aminoethyl nitrate nitrate (24.1)
  • Step B (S)-tert-butyl(2-(4-((((((2-(nitrooxy)ethyl)carbamoyl)oxy)methyl)phenyl)-3-oxo-3-(thio[2,3-c]pyridin-2-ylamino)propyl)carbamate (24.2)
  • Step C (S)-4-(3-amino-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl (2-(nitrooxy)ethyl)carbamate (Compound 24)
  • reaction was confirmed to be complete by TLC (bromocresol green color development).
  • Water was added to the reaction solution, extraction was performed with ethyl acetate (15 mL), the organic phases were separated and combined, and then the organic phases were washed with saturated saline water.
  • the organic phases were dried with anhydrous sodium sulfate, filtered, spin-dried, and purified by silica column to obtain white solid 25.1 (120 mg, yield: 58%).
  • Step B 4-((S)-3-(1,3-dioxoisoindolin-2-yl)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)propan-2-yl)benzyl (1r,3S)-3-(nitrooxy)cyclobutane-1-carboxylate (Compound 25.2)
  • Step C 4-((S)-3-amino-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)propan-2-yl)benzyl (1r,3S)-3-(nitrooxy)cyclobutane-1-carboxylate (Compound 25)
  • Example 25 was obtained (25 mg, yield: 30%, purity: 96%).
  • Step A (S)-4-(3-(1,3-dioxyisoindol-2-yl)-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 2-3-(nitrooxy)methyl-2-((nitrooxy)methyl)propionate (Compound 26.1)
  • Step B (S)-4-(3-amino-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 2-methyl-3-(nitrooxy)-2-((nitrooxy)methyl)propionate (Compound 26)
  • Step B trans-(S)-4-(3-((tert-butoxycarbonyl)amino)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)propane-2-yl)benzyl 4-((nitrooxy)methyl)cyclohexane-1-carboxylic acid (27.2)
  • Step C trans-(S)-4-(3-amino-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl4-((nitrooxy)methyl)cyclohexane-1-carboxylate (Compound 27)
  • Step A (3-bromophenethoxy)(tert-butyl)dimethylsilane (Compound 28.1)
  • Step B methyl 3-(2-(((tert-butyldimethylsilyl)oxy)ethyl)benzoate (Compound 28.2)
  • Step C 3-(2-(((tert-butyldimethylsilyl)oxy)ethyl)benzoic acid (Compound 28.3)
  • a mixed acid solution of concentrated nitric acid and concentrated sulfuric acid (20 drops of concentrated nitric acid, 4 drops of concentrated sulfuric acid) was added to 30 mL of dichloromethane under an ice-water bath. After stirring for 1 hour in the ice bath, compound 28.4 (250 mg, 1.5 mmol) was added to react at room temperature for 4 hours. The reaction was monitored to be complete by TLC. After the reaction was completed, water was added to quench the reaction, then extraction was performed with dichloromethane (40 mL ⁇ 2), and the organic phases were combined and washed with saturated saline water (30 mL ⁇ 3). The organic phases were dried with anhydrous sodium sulfate, filtered, spin-dried, and purified by column chromatography to obtain product 28.5 (235 mg, yield: 74%).
  • Step F (S)-4-(3-((tert-butoxycarbonyl)amino)-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 3-(2-(nitrooxy)ethyl)benzoate (Compound 28.6)
  • Step G (S)-4-(3-amino-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 3-(2-(nitrooxy)ethyl)benzoate (Compound 28)
  • Step A 2-(1-(hydroxymethyl)cyclopropyl)acetic acid (Compound 29.1)
  • Step B 2-(1-(((nitrooxy)methyl)cyclopropyl)acetic acid (Compound 29.2)
  • Step C (S)-4-(3-((tert-butoxycarbonyl)amino)-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 2-(1-((nitrooxy)methyl)cyclopropyl)acetate (Compound 29.3)
  • Step D (S)-4-(3-amino-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 2-(1-((nitrooxy)methyl)cyclopropyl acetate (Compound 29)
  • Step A 5-bromo-2,2-dimethylpentanoic acid (Compound 30.1)
  • Step B 2,2-dimethyl-5-(nitrooxy)pentanoic acid (Compound 30.2)
  • Step C 5-chloro-4,4-dimethyl-5-oxopentyl nitrate (Compound 30.3)
  • Step D (S)-4-(3-((tert-butoxycarbonyl)amino)-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 2,2-5-(nitrooxy)dimethyl valerate (Compound 30.4)
  • Step E (S)-4-(3-amino-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 2,2-dimethyl-5-(nitrooxy)valerate (Compound 30)
  • 6-bromohexanoic acid 500 mg, 2.56 mmol was dissolved in 8 mL of acetonitrile, and silver nitrate (871 mg, 5.13 mmol) was added to the reaction solution. Protected from light, and under an inert gas atmosphere, the reaction solution was stirred at 85° C. for 5 hours. The reaction was confirmed to be complete by TLC (bromocresol green color development). The precipitated solid in the reaction solution was filtered off with diatom, the filter cake was washed with acetonitrile, the filtrate was spin-dried, and the residue was dissolved in ethyl acetate.
  • Step B ((S)-4-(3-(1,3-dioxyisoindol-2-yl)-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 6-(nitrooxy)hexanoate (Compound 31.2)
  • Step C (S)-4-(3-amino-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)propan-2-yl)benzyl 6-(nitrooxy)hexanoate (Compound 31)
  • Step A 1-(hydroxymethyl)cyclopropanecarboxylic acid (Compound 32.1)
  • Step B 1-((nitrooxy)methyl)cyclopropanecarboxylic acid (Compound 32.2)
  • Step C (S)-4-(3-(1,3-dioxyisoindol-2-yl)-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 1-((nitrooxy)methyl)cyclopropanecarboxylic acid (Compound 32.3)
  • Step D (S)-4-(3-amino-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 1-((nitrooxy)methyl)cyclopropane carboxylate (Compound 32)
  • Step A (S,E)-3-(2,2-dimethyl-1,3-dioxolane-4-yl)methyl acrylate (Compound 33.1)
  • Step B methyl (S,E)-4,5-dihydroxypent-2-enoate (Compound 33.2)
  • Step D methyl (R)-4,5-bis(nitrooxy)valerate (Compound 33.4)
  • Step F 4-((S)-3-((tert-butoxycarbonyl)amino)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl(R)-4,5-bis(nitrooxy)valerate (Compound 33.6)
  • Step G 4-((S)-3-amino-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl(R)-4,5-bis(nitrooxy)valeric acid (Compound 33)
  • Step B (1S,3S)-dibenzylcyclobutane-1,3-dicarboxylate (Compound 34.2) and (1r,3r)-dibenzylcyclobutane-1,3-dicarboxylate (Compound 34.3))
  • Step C (1s,3s)-3-((benzyloxy)carbonyl)cyclobutanecarboxylic acid (Compound 34.4)
  • Step D (1s,3s)-benzyl-3-(hydroxymethyl)cyclobutanecarboxylate (Compound 34.5)
  • Step E (1s,3s)-3-(hydroxymethyl)cyclobutane carboxylic acid (Compound 34.6)
  • Step F (1s,3s)-3-((nitrooxy)methyl)cyclobutanecarboxylic acid (Compound 34.7)
  • Step G (1s,3R)-4-((S)-3-((tert-butoxycarbonyl)amino)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl benzyl 3-((nitrooxy)methyl)cyclobutanecarboxylate (Compound 34.8)
  • Step H (1s,3R)-4-((S)-3-amino-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)propane-2-yl)benzyl 3-((nitrooxy)methyl)cyclobutane-1-carboxylate (Compound 34)
  • Step B (1r,3r)-benzyl-3-(hydroxymethyl)cyclobutanecarboxylate (Compound 35.2)
  • Step D (1r,3r)-3-((nitrooxy)methyl)cyclobutanecarboxylic acid (Compound 35.4)
  • Step E (1r,3S)-4-((S)-3-((tert-butoxycarbonyl)amino)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl benzyl 3-((nitrooxy)methyl)cyclobutanecarboxylate (Compound 35.5)
  • Step F (1r,3S)-4-((S)-3-amino-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)propane-2-yl)benzyl 3-((nitrooxy)methyl)cyclobutane-1-carboxylate (Compound 35)
  • Step A 5,5-bis(bromomethyl)-2-phenyl-1,3-dioxane (Compound 36.1)
  • Step B diethyl 7-phenyl-6,8-dioxaspiro[3.5]nonane-2,2-dicarboxylate (Compound 36.2)
  • Step C 7-phenyl-6,8-dioxaspiro[3.5]nonane-2,2-dicarboxylic acid (Compound 36.3)
  • Step D 7-phenyl-6,8-dioxaspiro[3.5]nonane-2-carboxylic acid (Compound 36.4)
  • Step E 3,3-bis(hydroxymethyl)cyclobutane carboxylic acid (Compound 36.5)
  • Step F 3,3-bis((nitrooxy)methyl)cyclobutane carboxylic acid (Compound 36.6)
  • Step G (S)-4-(3-((tert-butoxycarbonyl)amino)-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 3,3-bis((nitrooxy)methyl)cyclobutane-1-carboxylate (Compound 36.7)
  • Step H (S)-4-(3-amino-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 3,3-bis((nitrooxy)methyl)cyclobutane-1-carboxylate (Compound 36)
  • Step A benzyl cyclopent-3-enecarboxylate (Compound 37.1)
  • Cyclopent-3-ene carboxylic acid (1 g, 8.93 mmol) was dissolved in 12 mL of N,N-dimethylformamide, and potassium carbonate (2.5 g, 17.86 mmol) and benzyl bromide (1.83 g, 10.72 mmol) were added. The reaction solution was stirred at room temperature overnight. Water (20 mL) was added to the reaction solution to dilute, and extraction was performed with ethyl acetate (40 mL) two times.
  • Step B benzyl (1R,3s, 5S)-6-oxabicyclo[3.1.0]hexane-3-carboxylate (Compound 37.2)
  • Step D (3R,4R)-3,4-dihydroxycyclopentanecarboxylic acid (Compound 37.4)
  • Step E (3R,4R)-3,4-bis(nitrooxy)cyclopentanecarboxylic acid (Compound 37.5)
  • Step F (3R,4R)-4-((S)-3-((tert-butoxycarbonyl)amino)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl benzyl 3,4-bis(nitrooxy)cyclopentanecarboxylate (Compound 37.6)
  • Step G (3R,4R)-4-((S)-3-amino-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)propan-2-yl)benzyl 3,4-bis(nitrooxy)cyclopentane carboxylate (Compound 37)
  • Step B (1R,4S)-4-((S)-3-((tert-butoxycarbonyl)amino)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl benzyl 4-((nitrooxy)methyl)cyclohexanecarboxylate (Compound 38.2)
  • Step C (1R,4S)-4-((S)-3-amino-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)propane-2-yl)benzyl 4-((nitrooxy)methyl)cyclohexanecarboxylic acid (Compound 38)
  • Step B (S)-1-(2-(nitrooxy)ethyl)pyrrolidine-2-carboxylic acid (Compound 39.2)
  • Step C (S)-4-((S)-3-((tert-butoxycarbonyl)amino)-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 1-(2-(nitrooxy)ethyl)pyrrolidine-2-carboxylate (Compound 39.3)
  • Step D (S)-4-((S)-3-amino-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)propan-2-yl)benzyl 1-(2-(nitrooxy))ethyl)pyrrolidine-2-carboxylate (Compound 39)
  • Step A (S)-4-(3-(1,3-dioxyisoindol-2-yl)-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 2-3-(nitrooxy)methyl-2-((nitrooxy)methyl)propionate (Compound 40.1)
  • reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL ⁇ 2). The organic phases were combined, washed with saturated saline water (30 mL ⁇ 5), dried with anhydrous sodium sulfate, filtered, spin-dried, and purified by column chromatography to obtain product 40.1 (157 mg, yield: 74%, light yellow solid).
  • Step B (S)-4-(3-amino-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 2-methyl-3-(nitrooxy)-2-((nitrooxy)methyl)propionate (Compound 40.2)
  • Step C (S)-4-(3-(dimethylamino)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)propan-2-yl)benzyl 2-methyl-3-(nitrooxy)-2-((nitrooxy)methyl)propionate (Compound 40)
  • Step A methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (Compound 41.1)
  • Step B 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (Compound 41.2)
  • the pH of the aqueous layer was adjusted to less than 4 with hydrochloric acid, extracted with ethyl acetate (20 mL ⁇ 2), and the organic phases were combined, dried with anhydrous sodium sulfate, filtered, spin-dried, and purified by column chromatography to obtain product 41.2 (287 mg, yield: 81%, white solid).
  • Step D (S)-4-(3-((tert-butoxycarbonyl)amino)-1-oxo-1-(thieno[2,3-c]pyridin-2-ylamino)propan-2-yl)benzyl 3-((nitrooxy)methyl)bicyclo[1.1.1]pentane-1-carboxylate (Compound 41.4)
  • Step E (S)-4-(3-amino-1-oxy-1-(thieno[2,3-c]pyridin-2-ylamino)prop-2-yl)benzyl 3-((nitrooxy)methyl)bicyclo[1.1.1]pentane-1-carboxylate (Compound 41)
  • the final concentration of each component of the ROCK2 reaction was: ROCK2: 1 nM, substrate: 500 nM, ATP: 6 uM, and the final concentration range of the test compounds was: 100 nM to 5 pM.
  • ROCK2 kinase inhibitor activities (IC 50 ) of the compounds detected by this method are as follows:
  • the A7R5 cells in the logarithmic growth phase were digested, 2E5 cells per well were inoculated in a 6-well plate and incubated overnight at 37° C. with 5% CO 2 , and the cell culture medium was replaced with a starvation medium containing 0.05% FBS after 24 hours. The cells were starved for 20 hours.
  • the cell activities (IC 50 ) of the compounds detected by this method are as follows:

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